Rats subjected to chronic constriction injury (CCI) of the sciatic nerve have been used as an animal model of reflex sympathetic dystrophy. Within three days, this injury results in ipsilateral sensory changes that are evident as characteristic pain behavior. The degree of development of pain sensitivity is assessed using standard procedures (von Frey hairs, pin prick, radiant heat and/or a cold stimulus). The high affinity cannabanoid antagonist, R(+)-WIN 55,212-2 mesylate, was found to alleviate the CCI-induced increased sensitivity to painful stimuli, suggesting that cannabanoid receptors may play a role in modulating this type of pain and may be useful in treatment of painful neuropathies in humans. The development of hyperalgesia is reported to be associated with an increased level of mRNA encoding nerve growth factor (NGF) and our results show that antibodies to NGF delay the appearance of pain behavior, whereas preimmune serum appears to enhance it. The involvement of immunological mechanisms is suggested by the observation that application f heat-aggregated keyhole limpet hemocyanin (KLH) to the left sciatic nerve of rats previously sensitized to KLH- induced long lasting bilateral thermal and mechanical hyperalgesia and allodynia. The sensory change appeared after several days, appearing first on the epsilateral and several days later on the contralateral side. The antigen was ineffective when applied to other areas or to the sciatic nerve of unsensitized rats. CD4 and CD8 lymphocyte infiltration and the appearance in the serum of affected animals of antibodies to sciatic nerve protein indicate involvement of an immunological mechanism as the basis for development of the neuropathic pain of CCI in rats.